Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
  • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
  • C07D513/04—Ortho-condensed systems

Definitions

• This invention relates to new intermediates, processes for preparing them, and their use in the preparation of 5-(4-pyridyl)-6-phenyl-2,3-dihydro- imidazo[2,1-b]thiazoles and corresponding thiazines which have activity as inhibitors of the 5-lipoxygenase pathway of arachidonic acid metabolism.
• the position isomers are separated with difficulty, and even the most efficient separation techniques, preferably using column separation, provide less than 50% yield of the preferred isomer. In practical fact, however, overall yields are much lower.
• the present invention greatly reduces the cost of chemical for the preparation of the biologically active 5-pyridyl-6-aryl compounds.
• the present invention provides compounds of the formula (I): in which:
• the compounds of the formula (I) are useful as intermediates in the preparation of biologically active final products which are 5-(4-pyridyl)-6-phenyl-2,3-dihydroimidazo[2,1-b]thiazoles and thiazines (hereinafter referred to as "biologically active final products"). All of the biologically active final products have activity as in vivo inhibitors of the 5-lipoxygenase pathway of arachidonic acid metabolism in animals, such as man and other mammals, and some are also useful as intermediates in the preparation of compounds which have activity as in vivo inhibitors of the 5-lipoxygenase pathway in animals such as man and other mammals (as disclosed in Bender et al., U.S.
• 7-(4-substituted phenyl)-2,3-dihydro-4H-imidazo [2,1-b]-(1,3)thiazines can be prepared by reacting the corresponding 2-amino-5,6-dihydro-4H-l,3-thiazine with 4-substituted bromo- acetophenones in a non-polar solvent such as benzene or chloroform, to form an intermediate which is then refluxed in water.
• a non-polar solvent such as benzene or chloroform
• the amino-thiazine starting material can be prepared by treating 3-bromopropylamine with t-butyl isothiocyanate, followed by reflux treatment with HBr or HC1. See, for example, Schubert, et al., Arch. Pharm., 301(10),750-762 (1968).
• the reaction (A) is carried out by reacting the 6-arylimidazo[2,1-b]thiazole or thiazine analog of Formula II with an excess of both the pyridine and the reactive acyl ester reactant in an organic solvent in which the reactants are soluble and with which the reactants, especially the acyl ester, are inert.
• the pyridine and acyl ester react to form the acylpyridinium reagent of Formula III in situ.
• the acylpyridinium reagent can be prepared separately in a solvent and then added to the solution of Formula II compound.
• Suitable solvents include methylene chloride, ethylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, ethyl ether, dioxane, toluene, or excess pyridine.
• reaction A the reaction mixture is cooled during the mixing of the reactants, preferably to a temperature between 5-20°C, by use of an ice/water bath. The mixture is then allowed to stand briefly at ambient temperature, followed by refluxing until reaction is complete. The reaction mixture is continually assayed using high performance liquid chromatography (HPLC) or thin layer chromatography (TLC) on aliquots to ascertain if unreacted Formula II compound is present. If so, additional acyl pyridinium salt is introduced. Other conditions of the reaction are.standard to the art.
• the resultant Formula I compounds can be recovered from the reaction mixture and isolated by standard techniques, or the reaction mixture (with no isolation of the Formula I compounds) can be used as the medium for the oxidation step described below as reaction (D).
• Reaction.(B) is conducted by contacting the Grignard reagent (Formula IV) with an excess of both the pyridine and the selected reactive acyl ester in a solvent appropriate for Grignard-reagent use.
• solvents include, but are not limited to, dry ethers such as ethyl ether, or preferably, tetrahydrofuran.
• the Grignard reagent can be combined with the pyridine and the acyl ester in sequence, or as in reaction (A) above, the pyridinium salt can be prepared separately and then added to the solution of Grignard reagent.
• the reaction is conducted by the addition of 2-6 moles of pyridine to each mole of the Grignard reagent, followed by addition of at least an equimolar amount of the acyl compound.
• the reactants are mixed into the solvent, with cooling, preferably to a temperature of -10°C or below.
• at least about 5 mole % of cuprous iodide (CuI) based on the molar quantity of pyridine present, is introduced to the reaction mixture to insure the ultimate addition of the Grignard reagent at the 4-position of the N-acyl-l,4-dihydropyridine compound.
• reaction initiates autogenously and the mixture can be permitted to warm to a temperature of about 20° C , but preferably no higher than about 15° C .
• Aliquots of the reaction mixture are extracted continuously and assayed using HPLC or TLC to determine the presence of unreacted imidazo[2,1-b]thiazole or thiazine.
• the conditions of the reaction are otherwise standard for those pertaining to G rignard synthesis in general.
• recovery and isolation can be effected by standard techniques, or the reaction mixture (without isolation of the Formula I compounds) can be used as the medium for the oxidation step of reaction (D) below.
• the Grignard reagents of Formula I V are novel compounds which embody another aspect of this invention.
• the Formula IV reagents are prepared by reaction (C): in which A, B, D, and R are as earlier defined; X' is Cl, Br, or I, preferably Br; X" is Cl or Br; and R is C 1 -C 5 alkyl, preferably butyl and most preferably n-butyl.
• the reaction (C) is conducted in an ether solvent, preferably tetrahydrofuran, at a temperature below O°C.
• the halogenated starting compound of Formula V is reacted with at least an equimolar amount of the alkyllithium compound at a temperature of from about -80°C to about -30°C.
• the magnesium halide etherate is added to the mixture in excess and reacted with the organolithium compound of Formula VI, during which the reaction temperature can be permitted to rise to a temperature up to about 0°C, although a reaction temperature below about -10°C is preferred.
• the Grignard reagent of Formula IV which is prepared in this manner is preferably used immediately in reaction (B), as described above. This is most easily effected by the addition of cuprous iodide and pyridine, followed by addition of the selected acyl ester to the final reaction mixture of reaction (C).
• the starting compounds of Formula V which are used in reaction (C) can be prepared by halogenating the 6-arylimidazo[2,l-b]thiazole or thiazine of Formula II described above. Halogenation is effected by standard techniques, which in general include treating the Formula II compound with Br 2 or Cl 2 in a neutral solvent at an elevated temperature.
• 5-bromo-6-phenyl-2,3-dihydroimidazo[2,1-b]thiazole can be prepared by reacting the unbrominated starting material of Formula II with an equimolar amount of Br 2 in methylene chloride at reflux temperature. See, S. Kano, Yakagaku Zasshi, 92, 51-58 (1972).
• the compounds of Formula I are preferably prepared with the most economical pyridinium salt reagents.
• reagents are those in which R 1 is ethoxy, methoxy, methyl, or phenyl.
• R 1 is ethoxy, methoxy, methyl, or phenyl
• A, B, and D are as described above
• R is H, C l -C 2 alkyl, C l -C 2 alkoxy, trifluoromethyl, N-azacycloalkyl of 5 or 6 carbon atoms, or halogen, preferably F, Cl, or Br.
• B and D are hydrogen
• A is -CH-(thiazole)
• R is F or Cl, particularly in the 4-position.
• Compounds of Formula I in which R 2 is hydrogen are intermediates that are formed in situ during the oxidation reaction (D), and as such they are not usually isolated during the reaction sequence, although isolation by standard techniques is possible if desired.
• the dihydropyridine of Formula I is reacted with an appropriate oxidizing agent in an inert solvent system until the starting material has been exhausted, as monitored, for example, by periodic TLC or HPLC analysis.
• the oxidizing agent is relatively mild, so as to avoid oxidizing the nuclear nitrogen or sulfur members to their respective oxide derivatives.
• Exemplary oxidation systems are sulfur (S 8 ) in decalin, tetralin, p-cymene, or xylene as solvent; or chloranil, oxygen gas, manganese oxide, ceric chloride, chromium oxide, hydrogen peroxide or ferricyanide in inert solvents.
• reaction conditions are reaction of a dihydropyridine with sulfur in refluxing xylene or with oxygen in the presence of tert.-butanol/potassium tert.-butoxide.
• the oxidation reaction proceeds rapidly, normally within one hour, at a temperature range of from ambient (about 23°C) for oxygen use, to solution reflux temperature, for sulfur use.
• the oxidized products of formula V II are isolated and purified using methods standard in the art.
• the reaction was then heated to 70° for 45 minutes. The reaction was allowed'to cool. The solvent was evaporated off in a rotary evaporator. The residue was treated with 10% potassium carbonate solution (25 ml). The mixture was extracted with methylene chloride (2 x 100 ml). The separated methylene chloride phase was dried over anhydrous sodium carbonate, filtered and concentrated in a rotary evaporator. The residue was dissolved in methylene chloride (1 ml) and poured into hexane (50 ml).
• the product was taken up in methylene chloride (100 ml) and extracted with 5% potassium carbonate solution (50 ml). The aqueous layer was back-extracted with methylene chloride (50 ml). The organic layers were combined, dried over sodium sulfate and filtered. The filtrate was concentrated in a rotary evaporator. The resulting oil was purified by silica gel chromatography (1:1, ether/hexane/2% methanol) to yield the 1,4-dihydro compound (300 mg, 40%) as a white crystalline solid, m.p. 139-141°.
• Section D The procedure of Section D is used to prepare other 5-hydrogen-6-substituted-imidazo[2,l-b]thiazole starting materials.
• 6-(4-Fluorophenyl)-2,3-dihydroimidazo[2,l-b]-thiazole (10.0 g, 0.0456 mol) and 11 ml (0.136 mol) of pyridine (previously stirred over potassium hydroxide) were dissolved in 150 ml of methylene chloride.
• pyridine previously stirred over potassium hydroxide
• 6-(4-Fluorophenyl)-2,3-dihydroimidazo[2,1-bl- thiazole(10.0 g, 0.0456 mol) and 11 ml (0.136 mol) of pyridine were dissolved in 150 ml of methylene chloride.
• To this cooled solution (10°) was added 20.35 g (0.13 mol) of phenyl chloroformate in 20 ml of methylene chloride under a nitrogen atmosphere. During the addition, the reaction pot temperature was not allowed to rise past 15°. After the addition, the reddish-colored solution was stirred at ambient temperature for 1.5 hours, then heated under reflux for an additional 15 minutes.
• 6-(4-Fluorophenyl)-2,3-dihydroimidazo(2,1-b]thiazole (45.0 g, 0.204 mol) and 55 ml (0.68 mol) of pyridine were dissolved in 500 ml of methylene chloride.
• a solution (10°) was added 91.3 g (0.65 mol) of benzoyl chloride in 100 ml of methylene chloride under a nitrogen atmosphere. During the addition, the reaction pot temperature was not allowed to rise past 10°. After the addition, the desired product precipitated from solution. The addition of the benzoyl chloride solution was continued. The resulting suspension was stirred at ambient temperature for 15 minutes, then heated to reflux for 15 minutes.
• the acidic layer was made basic with aqueous potassium carbonate and extracted with methylene chloride (3 x 50 ml). The organic layer was, then, dried and concentrated to yield 1.9 g (95%) of crude 5-(4-pyridyl)-S-(4-(fluorophenyl)-2,3-dihydroimidazo[2,1-b]-thiazole. Comparison with authentic material by TL C was used to verify the identity of the product; m.p. 189°.
• Example 6 Using the oxidation conditions of Example 6 for each of these dihydropyridyl compounds gives the respective 5-(4-pyridyl)-6-aryl-2,3-dihydroimidazo[2,1-b] thiazoles.
• the solution was allowed to warm to -30°C over a 45-minute period, and then held at that temperature for 10 minutes.
• the solution was then cooled to -50°C, and magnesium bromide etherate (2 mmol, 516 mg. 2 equiv) was added as a solid.
• the solution was allowed to warm to 0°C over a 30-minute period and held at that temperature for 15 minutes.
• the reaction mixture was then cooled to -20°C, copper iodide (20 mg) added, and the mixture maintained at -20°C for 10 minutes, after which dry pyridine (2.0 mmol, 158 mg) was added. After an additional 10 minutes, ethyl chloroformate (1.1 mmol, 119 mg) was added in a dropwise manner.

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• 1986
  • 1986-05-19 IL IL78834A patent/IL78834A/xx not_active IP Right Cessation
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• 1987
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